Neuron, Vol.
28, 343–347, November, 2000, Copyright 2000 by Cell Press
Toward a Neurobiology
of Obsessive-Compulsive Disorder
Ann M. Graybiel*‡ and Scott L. Rauch†
* Department of Brain and Cognitive Sciences
Massachusetts Institute of Technology
Cambridge, Massachusetts 02139
† Departments of Psychiatry and Radiology
Massachusetts General Hospital and
Harvard Medical School
Boston, Massachusetts 02114
OCD and OC-Spectrum Disorders
We all have habits and mannerisms, and some of these
are strong and urgent. But for the most part, these are
not intrusive behaviors; they are blended into our lives,
give us personality, and form a background on which
we build the much larger part of our cognitive activities.
Even when we engage in rituals, they can be like games,
as when children avoid stepping on cracks in the side-
walk. In people who suffer from obsessive-compulsive
disorder (OCD), such “habits,” “mannerisms,” and “ritu-
als” are out of control.
The name, OCD, comes from the hallmark signs and
symptoms of the disease, which affect both cognition
and motor behavior: obsessions, thoughts that repeat
over and over again, unwanted but insistent; and com-
pulsions to act, to repeat fragments of behavior over
and over in ritualistic, stereotyped succession. Typically,
particular compulsive acts are carried out in response
to a particular obsession, as if to neutralize the anxiety
and negative affect associated with that obsession. The
most common of these obsessions and compulsions
involve checking (going back over a behavior repeatedly
in response to obsessive self-doubts whether it was
done, and done just right), washing (for example, wash-
ing the hands until they bleed in response to the “obses-
sion” that they are dirty), ordering (straightening up, like
a child having to line up the shoes in his closet over and
over, or having to put them in sets of three), and fears
of performing aggressive or untoward behaviors and
repeated attempts to prevent this.
For the neurobiologist, key observations about these
symptoms include the following:
(1) People with OCD are usually aware that the obses-
sions and compulsions are nonsensical, but, despite
great effort, they cannot control them.
(2) The obsessions and compulsions usually are not
bizarre. They typically have possible or even ordinary
content.
(3) There is marked cross-cultural consistency in the
themes of the obsessions and compulsions, despite
heterogeneity in specific symptoms.
(4) Some patients suffer mainly obsessions, others
mainly compulsions, and still others both. Thus OCD
can express itself as primarily a cognitive-affective
disorder or primarily an executive-behavioral disorder.
‡ To whom correspondence should be addressed (e-mail: graybiel@
mit.edu).
Review
(5) The obsessions and compulsions can go on for
hours. For example, a “checker” checks, but cannot
be sure and has to check again and again. The ques-
tion “what if?” dominates, and there is no behavioral
closure.
These observations suggest that, in OCD, neural circuits
can trigger repetitive behaviors and thoughts that coex-
ist with others in conscious awareness, and suggest
that the triggering can be set off by what otherwise
would often be innocuous events.
Two other cardinal features of OCD are that it typically
has an early age of onset and that it very often is associ-
ated with comorbid conditions. Childhood onset OCD,
emerging before puberty, tends to affect males more
than females, tends to be related to motor tic disorders,
and may be severe and refractory to standard therapies.
Adult onset OCD peaks in the 20s, is more likely to affect
females, and tends to be more sensitive to treatment.
Worldwide, OCD is estimated to affect 1%–3% of the
population. Patients with OCD often suffer from other
anxiety disorders, including major depressive disorder,
which has a lifetime prevalence of 60%–70% in OCD
patients. It is the relationship between OCD and other
so-called OC-spectrum disorders, however, that has
had the greatest impact on ideas about the neurobiol-
ogy of OCD. Estimates of the rate of OCD (or “OC behav-
ior”) in patients with Tourette syndrome (TS) are as high
as 90%. This high cooccurrence, together with the
phenomenologic similarities between OCD and TS, has
prompted the hypothesis that these disorders may be
closely linked in terms of genetics and pathophysiology.
Other so-called OC-spectrum disorders include tricho-
tillomania (characterized by compulsive hair-pulling be-
havior) and body dysmorphic disorder (characterized by
obsessions with specific aspects of one’s own appear-
ance and ritualistic attempts to modify it). Little is known
about the neurobiology of these disorders.
Evidence for Cortico-Basal Ganglia Circuit
Dysfunction in OCD
There is no known overt locus of neuronal degeneration
in OCD as there is, for example, in Parkinson’s disease
or Huntington’s disease. However, functional imaging
studies suggest that in OCD patients, there is abnormal
metabolic activity in the orbitofrontal cortex, the anterior
cingulate/caudal medial prefrontal cortex, and the cau-
date nucleus (the anterior part of the striatum) (Rauch
and Baxter, 1998; Saxena et al., 1998). Activity within
this cortico-basal ganglia network (sometimes called
the “OCD circuit”) is increased at rest relative to that in
controls, is accentuated during provocation of symp-
toms, and is attenuated following successful treatment.
This neuroimaging evidence supports earlier sugges-
tions of basal ganglia involvement in OCD based on the
fact that focal lesions in the striatum or in its target
structure, the pallidum, can produce striking OCD-like
behavior (Laplane et al., 1989).
Dysfunction of the basal ganglia and associated cor-
Neuron
344
tico-basal ganglia circuits may be a common neural
feature of OCD and OC-spectrum disorders including
TS. For example, in TS, activity in the prefrontal cortex
and the caudate nucleus is increased, and activity in
the putamen and the pallidum is decreased when active
efforts are made to suppress tics (Peterson et al., 1998).
Neurobiology of the OCD Circuit
What features of the cortico-basal ganglia circuits link-
ing the orbitofrontal and anterior cingulate cortex to the
caudate nucleus might account for the cardinal features
of OCD? Based on the effects of lesions in humans and
experimental animals and on the results of single-unit
electrophysiological recordings, all three of these struc-
tures have been implicated in the evaluation of the signif-
icance of stimuli as positive or negative (rewarding or
punishing). All three have also been linked to aspects of
executive function. Finally, cortico-basal ganglia circuits
have been suggested to form a neural system critical
for habit learning and for the routine performance of
habits, and structures of the OCD circuit have specifi-
cally been implicated in the acquisition of stereotyped
behaviors.
Orbitofrontal Cortex
Lesions involving the orbitofrontal cortex in humans lead
to deficits in behavioral planning and decision making
based on estimates of the positive or negative conse-
quences of particular actions (Damasio et al., 1990). In
monkeys, neurons in the orbitofrontal cortex modulate
their activity in relation to the motivational value of stim-
uli and the reward preferences of the animal, and orbito-
frontal lesions result in selective abnormalities in reward
expectancy and preferences (Rolls, 1996; Tremblay and
Schultz, 1999). In what has come to be called the so-
matic marker hypothesis, Damasio and his colleagues
suggest that exposure to particular stimuli or contexts
reactivate somatic states (autonomic responses, as indi-
cated in their experiments by galvanic skin responses)
that, through experience, have become associated with
the stimuli. They propose that in OCD, this reactivation
of somatic markers in response to expected outcomes
becomes excessive, driving the behavioral repetition.
Support for this general view of orbitofrontal cortex
function comes from studies by the Damasio group on
the behavior of patients with restricted ventromedial
frontal cortex lesions in gambling tasks. Even knowing
the “odds,” these patients were unable to make the
winning response. Elliott and colleagues (Elliott et al.,
1999) have shown with functional magnetic resonance
imaging that in such gambling tasks, activity in the orbi-
tofrontal cortex is unique in being proportional to the
uncertainty of outcomes.
Anterior Cingulate Cortex
The anterior cingulate cortex and adjoining medial pre-
frontal cortex are strongly interconnected with the orbit-
ofrontal cortex and structures of the limbic system and,
like the orbitofrontal cortex, have been implicated by
lesion, recording and imaging studies in motivation and
affective behavior, and in major depression as well as
OCD (Price et al., 1996; Weeks et al., 1996). There is a
fairly direct route from the anterior cingulate cortex to
the motor cortex. The anterior cingulate cortex sends
direct anatomical connections to the rostral cingulate
motor area, and this cortical area in turn projects to
the motor cortex (Picard and Strick, 1997). Restricted
chemical lesions of the rostral cingulate motor area ren-
der monkeys incapable of selecting an action based on
the reward contingencies associated with it (Shima and
Tanji, 1998). As part of a cortical network, then, the
orbitofrontal cortex and anterior cingulate cortex could
together exert a powerful influence both on the per-
ceived emotional value of stimuli and on the selection
of behavioral responses based on these experience-
based expectancies and perceived outcomes.
The Basal Ganglia
How could the basal ganglia influence this network? The
neocortex and basal ganglia are connected by parallel
loops or families of cortico-basal ganglia connections.
The basal ganglia are thought to exert control over ac-
tion release through antagonistic “push–pull” output
pathways, which serve to select intended actions. These
functions are disrupted in hypokinetic disorders such
as Parkinson’s disease, in which action is diminished,
and in hyperkinetic disorders such as Huntington’s dis-
ease, in which action is excessive. It has been suggested
that, by analogy, dysfunction of these cortico-basal gan-
glia pathways may also occur in some neuropsychiatric
disorders, including OCD and TS (Swerdlow and Koob,
1987).
Different sets of cortico-basal ganglia loops are
thought to have specialized functions depending on the
cortical areas participating in the loops (Alexander et al.,
1990). This organization may account for the symptom
specificity of OCD and OC-spectrum disorders. For ex-
ample, in TS, in which repetitive tics or actions are the
predominant symptoms, the “motor loop” through the
putamen is more affected than it is in OCD according
to neuroimaging data. In OCD, which typically involves
obsessions as well as compulsive actions, the neural
circuits interconnecting the orbitofrontal and anterior
cingulate cortex with the basal ganglia are involved.
In addition to loop topography, special features of the
OCD circuit may contribute to its effects on behavior.
Both the orbitofrontal and anterior cingulate cortex pro-
ject to the ventral part of the caudate nucleus and to
the ventral striatum. In the monkey, these regions have
been found to send outputs not only to the pallidum, but
also to a large part of the dopamine-containing substan-
tia nigra pars compacta, from which the nigrostriatal
tract originates. Haber and colleagues suggest that
these limbic system-related basal ganglia connections
do not follow the segregated loop plan completely, with
the result that limbic outflow can affect a wide part of
the striatum (Lynd-Balta and Haber, 1994). Moreover, the
caudal orbitofrontal and anterior cingulate/caudal me-
dial prefrontal cortex are also the main source of input
to the striosomal system in the head of the caudate
nucleus (Eblen and Graybiel, 1995). Striosomes in this
region have been linked to reward effects (Aosaki et al.,
1995; White and Hiroi, 1998), and they appear to be
differentially active under conditions in which the ani-
mals perform repetitive, stereotyped behaviors in re-
sponse to dopamine receptor agonists (Canales and
Graybiel, 2000).
These special features of orbitofrontal and anterior
cingulate cortico-basal ganglia circuits could be impor-
tant not only for understanding OCD and OC-spectrum
Review
345
symptomatology, but also for understanding develop-
mental aspects of these disorders. Striatal circuits de-
velop according to gradients, and for a prolonged period
the orbitofrontal/cingulate-linked striosomal system and
ventral regions lead the rest of the caudate-putamen
complex in their maturational state.
OCD and Chunking Functions of Cortico-Basal
Ganglia Circuits
One hypothesis emerging from these findings is that the
basal ganglia may influence both motor pattern genera-
tors in the brainstem and spinal cord and “cognitive
pattern generators” in the cerebral cortex. By this view,
the loops running from the neocortex to the basal gan-
glia and then to the thalamus and back to the neocortex
may help to establish cognitive habits, just as they may
influence the development of motor habits (Graybiel,
1997). If so, the cortico-basal ganglia loop dysfunction
in OCD could reflect both sides of basal ganglia function,
motor and cognitive, to bring about repetitive actions
(compulsions) and repetitive thoughts (obsessions).
Another hypothesis proposed about the basal ganglia
is that they help to recode cortical and other inputs into
a form that allows actions to be released as “chunks”
or sequences of behavior (Graybiel, 1998). This function,
under normal conditions, could be important in forming
coordinated, sequential motor actions and in developing
streams of thought and motivation. The architecture of
cortico-basal ganglia circuitry could support the smooth
progression from a cognitive framework establishing
priorities for potential behaviors to behavioral selection,
which in turn would facilitate fluid and adaptive behav-
ioral output. Conversely, dysfunction of this cortico-
basal ganglia system could contribute to the symptoms
of OCD patients: they become stuck in a conceptual
framework, unable to shift from one priority set to the
next, and thus remain locked into a specific behavioral
output program. The “what if” doubts and anxiety suf-
fered by the OCD patient may indicate a lack of loop
closure between expected outcomes and the chunks of
behavior that should generate them.
A large part of the frontal cortex receives inputs from
the basal ganglia conveyed via the thalamus. These
same cortical regions not only project to the basal gan-
glia (mainly to the striatum) but also project to other
brain regions including the thalamus. Cortico-thalamic
loops are thought to be critical for cortical functioning.
If the basal ganglia form associations among cortical
inputs on the basis of context and evaluative signals,
and thereby promote automation of selected behaviors,
they could relieve the frontal cortex of a substantial
computational load in carrying out executive functions.
With both corticothalamic and cortico-basal ganglia
systems functioning under normal conditions, parallel
processing could then occur with the corticothalamic cir-
cuits supporting conscious (explicit) information proc-
essing and cortico-basal ganglia supporting automatic
(implicit) processing functions. If cortico-basal ganglia
pathways become abnormal, as appears to be true in
OCD, such parallel processing capabilities would be
compromised. Information normally processed auto-
matically could intrude into the conscious domain as
obsessions, and behavioral selection could become nar-
rowed to compulsive acts. Such dysfunction could con-
tribute to the compelling nature of obsessions in OCD
and to the stereotypic behaviors carried out as compul-
sions.
Toward a Neurobiology of OCD
To date, work on the neurobiology of OCD and OC-spec-
trum disorders has advanced to the point of suggesting
that cortico-basal ganglia circuits are dysfunctional in
OCD, but neither the mechanisms nor the genetics and
epidemiology of these disorders are understood. There
is a great opportunity for further research bringing to-
gether molecular and systems neuroscience with clinical
studies of these disorders. We mention here important
issues to be addressed.
What Is the Lesion in OCD? When Does It Occur?
And How Are Its Effects Counteracted by Treatment?
There is a clear need to understand more about the
neuropathology of OCD. If lesions of the striatum can
induce intense compulsive behaviors and stereotypies,
does this mean that there are subtle lesions of the stria-
tum in OCD that conventional methods have failed to
pick up? Magnetic resonance spectroscopy is begin-
ning to suggest reduced N-acetylaspartate within the
striatum of persons with OCD, so that neuronal density
there may actually be reduced (Fitzgerald et al., 2000).
Short of cell death, abnormal brain chemistry in OCD
could affect neurotransmission in cortico-basal ganglia
circuits, leading to the abnormal metabolic activity seen
in imaging studies. Very little is known about the neuro-
chemistry of OCD, but a clue may come from the fact that
the most successful pharmacologic therapy for OCD
is treatment with inhibitors of serotonin reuptake sites
(SRIs). Effective therapy with SRIs can in part reverse
the abnormal metabolic activity seen in this OCD circuit,
suggesting that the modulatory effects of serotonin can
act on the cortico-basal ganglia circuit defined in scan-
ning studies.
Despite this clinical result, strong evidence of a pri-
mary serotonergic or other neurotransmitter abnormality
in OCD is lacking. One suggestion is that SRIs have
their beneficial effects via downregulation of 5HT-1D
autoreceptors within orbitofrontal cortex (El Mansari et
al., 1995). In animal studies, these receptor changes
have been shown to follow the time course of antiobses-
sional therapeutic effects (8 weeks) in the orbitofrontal
cortex, but to follow the time course of antidepressant
therapeutic effects (4 weeks) within dorsolateral pre-
frontal cortex. This temporal difference is interesting
given that these two regions of the frontal cortex have
been implicated by functional imaging studies in OCD
and major depressive disorder, respectively. Although
cortico-basal ganglia circuit dysfunction may be com-
mon to OCD and TS, however, different neurotransmitter
systems in these circuits may be critical in modulating
their different symptom complexes, at least as judged
by pharmacotherapy. In contrast to OCD, in TS it is
dopamine receptor antagonists (principally D2 class re-
ceptor antagonists) that appear to be the most effective
agents for reducing tic frequency. In cases of OCD with
comorbid tics also, but not in OCD cases without tics,
the efficacy of SRIs may be boosted by the addition of
dopamine receptor antagonist treatment (McDougle et
al., 1994).
Neuron
346
What Are the Genetics of OCD? Can Environmental
Factors Induce OCD? Do Common Etiologic
Mechanisms Underlie OCD and OC-Spectrum
Disorders Such as TS?
OCD is familial and so is TS. Some studies have sug-
gested that OCD and TS represent different phenotypic
expressions of the same genetic vulnerability. The ge-
netics of OCD is not yet understood, but there is now
a coordinated international effort, by the Tourette Syn-
drome International Consortium for Genetics, to identify
susceptibility genes for TS. Finding out about the genet-
ics of TS should help at least to narrow the search for
genetic factors in OCD and, given the frequent comor-
bidity of the two disorders, may yield candidate genes
for OCD as well. If so, there would be the chance to
identify the molecular basis for OCD dysfunction.
There are also potential etiologic links between OCD
and OC-spectrum disorders based on the possibility
that OCD and OC-spectrum disorders can occur as a
result of infection. This idea was proposed by von Eco-
nomo, who described patients suffering from obses-
sions and compulsions in the wake of the great 1917
epidemic of viral encephalitis in Europe. This proposal
has received new impetus from the work of Swedo and
colleagues (Swedo et al., 1998), who have studied disor-
ders precipitated by rheumatic fever, caused by type A
␤-hemolytic streptococcal infection. Such infections
can lead to Syndenham’s chorea, itself characterized
by symptoms including obsessions, compulsions, and
tics, and to OCD-like syndromes. This group of disorders
has been termed Pediatric Autoimmune Neuropsychiat-
ric Disorders Associated with Strep (PANDAS). Their
underlying pathology is thought to involve an autoim-
mune-mediated attack on the striatum precipitated by
the streptococcal infection. Altogether, then, current ev-
idence suggests that there may be susceptibility genes
for OCD and OC-spectrum disorders as well as environ-
mental factors precipitating these disorders—and that
their interactions, when understood, may lead to new
forms of successful therapy.
What Are the Dynamics of Cortico-Basal Ganglia
Circuit Function during the Expression
of OCD Symptoms?
Even though neuroimaging studies have pointed to cor-
tico-basal ganglia circuits as being dysfunctional in
OCD, it is still not clear what the functional abnormality
is in these circuits in OCD and how they contribute to
the expression of OCD symptoms. Nor is it clear how
these circuits work normally, or how the multiple loops
of this system interconnecting the cortex, thalamus and
basal ganglia actually operate. Improvements in the
temporal and spatial resolution of imaging will soon
make it possible to follow the cascade of neural activity
changes that occur during the evolution of OCD symp-
toms. Then it should be possible to identify brain sites
participating in the buildup of an obsession, the atten-
dant anxiety, the escalation of an urge, the performance
of a compulsion, and the resolution of the obsession
and accompanying anxiety. This would for the first time
allow detection of the dynamics of activity in circuits
active in the expression of OCD symptoms. Advances
in imaging with magnetic resonance spectroscopy and
labeled receptor and other ligands should also help to
clarify the neurochemistry of the disorder.
Are Some OCD Behaviors Learned or Conditioned?
There is no clear answer to this question, but what is
known is that in some OCD patients, partial reversal
of OCD symptoms and abnormal cortico-basal ganglia
circuit activity can be achieved by behavioral therapy
in which patients are exposed systematically and under
supervision to the very stimuli that otherwise provoke
obsessions and compulsions (Baxter et al., 1992). This
evidence strongly suggests that studies of learning and
memory mechanisms in relation to the development of
repetitive behaviors may help in understanding the neu-
robiology of OCD. Interestingly, different levels of re-
sponsivity to either behavioral therapy or pharmacologic
therapy have even been observed in groups of OCD
patients, and these have been correlated with different
levels of metabolic activity in the orbitofrontal cortex
and anterior cingulate cortex (Brody et al., 1998). Such
clinical data suggest that the OCD population may be
heterogeneous and that experience-based plasticity
may differentially affect the “OCD circuit” in some pa-
tients. More generally, these findings raise the possibility
that, in addition to susceptibility genes for OCD, environ-
mental factors may be important in determining the
emergence of particular types of OCD symptoms in dif-
ferent patients.
Are the Obsessions and Compulsions in OCD
Exaggerated Forms of Habits of Thought
and Action?
Even if imaging studies identify the cascades of activity
in cortico-basal ganglia circuits occurring during ex-
pression of OCD symptoms, it still will be unclear what
form of neural encoding is responsible for the symptoms
or for their resolution. One interesting possibility is that
the neural circuits that normally mediate habits and au-
tomated behaviors become hyperactive or inaccessible
to a stop signal in OCD and related disorders. Three
recent models for studying what goes on in cortico-
basal ganglia circuits when habits are formed are perti-
nent here. In the first, monkeys were taught a sensorimo-
tor conditioning task in which light or sound cues were
associated with reward, and recordings were made from
the tonically active neurons of the striatum thought to
be the cholinergic interneurons. As the monkeys learned
the task, the neurons acquired responses to the condi-
tioning stimuli, and they maintained those responses as
long as dopamine was present in the striatum. Removal
of dopamine reduced the acquired responses (Aosaki
et al., 1994a, 1994b), and so did inactivation of the intra-
laminar thalamus (Matsumoto et al., 2000). In related
work, removal of dopamine in the striatum before learn-
ing of a simple sequential push-button task prevented
the task from being executed without cues as a unified
behavioral sequence (Matsumoto et al., 1999). In the
second set of experiments, the activity of projection
neurons in the sensorimotor striatum of rats was moni-
tored with chronically implanted tetrodes. The ensemble
activity of these neurons was found to undergo large-
scale and long-lasting changes as the rats learned the
procedure and then performed it after learning (Jog et
al., 1999; see also Carelli et al., 1997). These studies
suggest that, with experience, striatal neurons can de-
velop new responses to environmental stimuli. Given
the activity changes in striatal projection neurons, this
plasticity is likely to affect basal ganglia outputs and
Review
347
thus cortico-basal ganglia loop function. In the third
set of experiments, the expression of stereotypies in-
duced in rats by repeated doses of psychomotor stimu-
lant drugs was found to be closely correlated with
heightened activation of the striosomal compartment of
the striatum—the compartment preferentially intercon-
nected with the anterior cingulate and orbitofrontal cor-
tex (Canales and Graybiel, 2000). Such experiments
highlight the potential for identifying the changes in neu-
ronal activity that occur in cortico-basal ganglia circuits
as repetitive action repertoires come to dominate be-
havior. A first step toward testing whether such striatal
function could be affected in OCD has been carried out
by testing people with OCD on implicit learning tasks that
normally activate the striatum. Striatal activation was
found to be deficient in the OCD subjects, but activation of
the hippocampal system (normally recruited during explicit
learning tasks) was abnormally high (Rauch et al., 1997).
Coordination of human brain imaging of this sort with
laboratory-based experiments holds great promise for
uncovering the neurobiology of OCD.
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